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ATR and PKMYT1inhibition re-sensitize a subset of TNBC patient-derived models to carboplatin and induce mitotic catastrophe

ABSTRACT: Triple negative breast cancer (TNBC) is associated with poor prognosis and is mainly treated with chemotherapy-based regimens, often including carboplatin. Resistance to carboplatin is a common clinical issue that is either initially present or develops with treatment. Overcoming this resistance is a significant clinical challenge, which highlights the need for novel therapeutic strategies. We used a pooled shRNA screening approach with a chemoresistant TNBC patient-derived xenograft (PDX) cell (PDXC) line to identify targets whose knockdown would enhance the efficacy of carboplatin. This screening led to the identification of the ATR (ataxia telangiectasia and Rad3-related) gene as a key therapeutic vulnerability. Inhibiting ATR with BAY1895344 or AZD6738 re-sensitized carboplatin-resistant PDXCs and PDXs to carboplatin, resulting in an increase in DNA damage, and apoptosis. ATR inhibition prevents carboplatin-resistant cells from effectively engaging the S and G2/M checkpoints required for DNA repair, leading to mitotic catastrophe. We further identified that the addition of ATR inhibitors to carboplatin enabled FOXM1-targeted gene program leading to premature passage into mitosis. Moreover, targeting PKMYT1, a regulator of cyclin-dependent kinase 1 (CDK1) controlling the G2/M checkpoint, through knockdown or with the novel PKMYT1 inhibitor RP-6306, also enhanced carboplatin efficacy in our TNBC PDXC. Molecular factors associated with response to the ATR inhibitor/carboplatin combination included low RNA levels of PKMYT1. These results underscore the pivotal roles of ATR and PKMYT1 in mediating resistance to carboplatin in TNBC and support targeting these pathways to overcome carboplatin resistance in this disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE325338 | GEO | 2026/03/27

REPOSITORIES: GEO

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Project description:Targeting cell cycle checkpoints has emerged as a promising strategy in cancer therapy, yet single-agent inhibitors often fail due to compensatory mechanisms. Here, we demonstrate that co-inhibition of ATR (RP-3500) and PKMYT1 (RP-6306) induces synthetic lethality in Rb1-deficient breast cancers by disrupting both S/G2 and G2/M checkpoints, resulting in replication stress, premature mitotic entry, and DNA damage accumulation. In vitro, Rb1-deficient breast cancer cell lines exhibited marked apoptosis and loss of clonogenic potential, whereas Rb1-proficient models remained largely resistant to combination treatment. Genetic manipulation of Rb1 confirmed this dependency: Rb1 knockdown sensitized resistant models, and overexpression conferred protection. In vivo, patient-derived xenograft (PDX) models recapitulated these findings. Rb1-deficient tumors underwent complete regression, while Rb1-proficient tumors showed limited response with RP-3500/RP-6306 treatment. Combination therapy was well tolerated in vivo, without significant toxicity or weight loss. Biomarker analysis revealed increased γH2AX and reduced Ki67 staining exclusively in Rb1-deficient PDX models, underscoring the specificity of this response. Mechanistically, Rb1 loss impaired double-strand DNA repair by attenuating homologous recombination and non-homologous end joining, leading to replication fork collapse, chromosomal instability, and mitotic catastrophe. Proteogenomic analysis identified JNK/p38 stress response pathway activation as a key driver of apoptosis following ATR/PKMYT1 inhibition in Rb1-deficient cells. Clinically, analysis of stage IV breast cancer patient datasets revealed that Rb1-low tumors display reduced DNA repair pathway activity and are enriched in triple-negative and CDK4/6 inhibitor-resistant luminal breast cancers. These findings establish Rb1 loss as a functional biomarker for ATR/PKMYT1-targeted therapy, offering a precision treatment strategy for advanced breast cancers.

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ATR and PKMYT1inhibition re-sensitize a subset of TNBC patient-derived models to carboplatin and induce mitotic catastrophe

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